title: Pharmacokinetic interaction between ivabradine and carbamazepine in healthy volunteers.
abstract: OBJECTIVE
  Ivabradine is a novel heart rate-lowering agent that selectively and specifically inhibits the depolarizing cardiac pacemaker If current in the sinus node. Our objective was to evaluate a possible pharmacokinetic interaction between ivabradine and carbamazepine in healthy volunteers.
  
  
  METHODS
  The study consisted of two periods: Period 1 (Reference), when each volunteer received a single dose of 10 mg ivabradine and Period 2 (Test), when each volunteer received a single dose of 10 mg ivabradine and 400 mg carbamazepine. Between the two periods, the subjects were treated for 15 days with a single daily dose of 400 mg carbamazepine. Plasma concentrations of ivabradine were determined during a 12-h period following drug administration, using a high-throughput liquid chromatography with mass spectrometry analytical method. Pharmacokinetic parameters of ivabradine administered in each treatment period were calculated using non-compartmental and compartmental analysis to determine if there were statistically significant differences.
  
  
  CONCLUSIONS
  In the two periods of treatments, the mean peak plasma concentrations (C(max)) were 16·25 ng/mL (ivabradine alone) and 3·69 ng/mL (ivabradine after pretreatment with carbamazepine). The time taken to reach C(max), t(max), were 0·97 and 1·14 h, respectively, and the total areas under the curve (AUC(0-∞)) were 52·49 and 10·33 ng h/mL, respectively. These differences were statistically significant for C(max) and AUC(0-∞) when ivabradine was administered with carbamazepine, whereas they were not for t(max), half-life and mean residence time.
  
  
  CONCLUSIONS
  T Carbamazepine interacts with ivabradine in healthy volunteers, and lowers its bioavailability by about 80%. This magnitude of effect is likely to be clinically significant.
authors.affiliation: Faculty of Pharmacy, Department of Pharmaceutical Technology and Biopharmaceutics, University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca, Romania. Laurian.Vlase@umfcluj.ro
authors.forename: L
authors.initials: L
authors.lastname: Vlase
authors.forename: M
authors.initials: M
authors.lastname: Neag
authors.forename: A
authors.initials: A
authors.lastname: Popa
authors.forename: D
authors.initials: D
authors.lastname: Muntean
authors.forename: I
authors.initials: I
authors.lastname: Bâldea
authors.forename: S E
authors.initials: SE
authors.lastname: Leucuta
mesh_terms: D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001552:Benzazepines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D002220:Carbamazepine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004347:Drug Interactions; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D000077550:Ivabradine; D008297:Male; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D001552:Benzazepines; D002317:Cardiovascular Agents; D002220:Carbamazepine; D000077550:Ivabradine